Human papillomaviruses (HPV) exhibit species and tissue specificity. They induce benign proliferative lesions, and the viruses may be further characterized in that only a subset of over 65 to 70 different papillomaviruses are associated with lesions that can progress to malignancy. Transfection of recombinant HPV of the high-risk clinical type into genital epithelia results in immortal cells expressing the relevant HPV genes, but malignancy does not occur when the cells are injected into immunodeficient mice. Thus, one of the Laboratory's primary concerns is the role of HPVs in the progression of benign lesions to malignant lesions. The viral genome is usually found integrated in HPV- 16- and HPV-18- associated cervical cancers, a situation identical to that which occurs with the addition of recombinant HPV. The report that the ras gene may be amplified and its expression increased in advanced cervical cancer suggests the involvement of cellular oncogenes in some step of tumor progression. The addition of recombinant v-Ha-ras to genital keratinocytes results in the conversion of immortalized cells containing HPV to cells that produce invasive carcinomas when injected into immunological-deficient mice. Change in keratin pattern also paralleled the in vivo situation. Whereas cervical normal squamous cells have a K14 characteristic of the malignant cells which is a loss of K14, the malignant cells obtained after ras exhibited uncoupling of the K14 and K5. This downregulation of K14 may be a good molecular marker for cervical carcinomas. Because HIV and HPV infections are both, in part, sexually-transmitted diseases, factors that influence one may influence the other. Current experiments demonstrate that human herpesvirus-6 is capable of upregulating HIV and that it may have a direct affect on expression of HPVs. Furthermore, preliminary data suggests that herpesvirus-6 and HPV may be found in the same spontaneous cervical cancers. The molecular and cell biology of such interactions represent a major focus of this project.